Solid oral pharmaceutical compositions for isoxazoline compounds

ABSTRACT

A solid oral pharmaceutical composition for delivery of a pharmaceutically acceptable active ingredient to an animal where the composition comprises an isoxazoline compound, a solvent and an excipient, a process for the manufacture of such solid oral pharmaceutical composition and a method of controlling a parasite infection administering such solid oral pharmaceutical composition.

BACKGROUND OF THE INVENTION

A number of parasites can infest or infect domestic animals especiallyalso companion animals such as cats and dogs. These pests and parasitesare of great nuisance to both the animals and their owners.

Isoxazoline compounds are known in the art and these compounds and theiruse as antiparasitic are described, for example, in US patentapplication US 2007/0066617, and International Patent applications WO2005/085216, WO 2007/079162, WO 2009/002809, WO 2009/024541, WO2009/003075, WO 2009/080250, WO 2010/070068 and WO 2010/079077, thedisclosures of which, as well as the references cited herein, areincorporated by reference.

This class of compounds is known to possess excellent activity againstectoparasites, i.e. parasitic insect and acarids, such as ticks andfleas and endoparasites such as nematodes.

Examples of isoxazoline compounds are carbamoyl benzamide phenylisoxazoline (CBPI) compounds. A specific example of a CBPI compound is4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(CAS RN [864731-61-3])—USAN fluralaner.

The CBPI compound fluralaner is disclosed in patent application WO2005/085216.

As these isoxazoline compounds have been originally investigated fortheir use in the agricultural area it is necessary to identify specificformulations that allow their veterinary use, i.e. safe administrationto control parasites in animals effectively.

One known and convenient way of administering an ectoparasiticidecompound to an animal is oral administration, e.g. as solid oralformulation such as tablets or soft chews that have a highbioavailability to allow the control of parasites with a low dosage ofthe ectoparasiticide compound orally administered to the animal.

SUMMARY OF THE INVENTION

In one aspect the current invention is directed to a solid oralpharmaceutical composition comprising an effective amount of at leastone isoxazoline compound of the Formula (I)

wherein

R¹=halogen, CF₃, OCF₃, CN,

n=integer from 0 to 3, preferably 1, 2 or 3,

R²=C₁-C₃-haloalkyl, preferably CF₃ or CF₂Cl,

T=5- or 6-membered ring, which is optionally substituted by one or moreradicals Y,

Y=methyl, halomethyl, halogen, CN, NO₂, NH₂—C═S, or two adjacentradicals Y form together a chain, especially a three or four memberedchain;

Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals;

X=CH₂, CH(CH₃), CH(CN), CO, CS,

R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃);

R⁴=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl,haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl,propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl,methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl,ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl;

or R³ and R⁴ together form a substituent selected from the groupconsisting of:

or a salt or solvate thereof, a solid carrier and a solvent, wherein thesolvent is selected from 2-pyrrolidone, dimethylacetamide or mixturesthereof.

In a preferred embodiment the solid oral pharmaceutical composition is asoft chewable veterinary pharmaceutical composition for oraladministration.

In a preferred embodiment the solid carrier is microcrystallinecellulose.

In one embodiment the composition further comprises pamoic acid or apharmaceutically acceptable salt thereof.

In one embodiment the isoxazoline compound is fluralaner.

In one embodiment the isoxazoline compound is4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.

In one embodiment the isoxazoline compound is afoxolaner.

In one embodiment the isoxazoline compound is4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.

In one embodiment the isoxazoline compound is5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.

In one embodiment the solid oral pharmaceutical composition comprises anadditional pharmaceutically active compound.

In one embodiment the additional pharmaceutically active compound is amacrocyclic lactone selected from the group of ivermectin, milbemycin,and moxidectin.

In one embodiment the solid oral pharmaceutical composition comprises anisoxazoline compound of Formula (I) or a salt or solvate thereof,2-pyrrolidone, microcrystalline cellulose, sodium starch glycolate,sodium lauryl sulfate, sodium pamoate, magnesium stearate, aspartame,glycerol, soybean oil, and polyethylene glycol

In another embodiment the solid oral pharmaceutical compositioncomprises an isoxazoline compound of Formula (I) or a salt or solvatethereof, dimethyl acetamide, microcrystalline cellulose, sodium starchglycolate, sodium lauryl sulfate, sodium pamoate, magnesium stearate,aspartame, glycerol, soybean oil, and polyethylene glycol.

Another aspect of the invention is a method of preparing a solidpharmaceutical composition comprising dissolving the isoxazolinecompound as above in the solvent and then adsorbing the resultingsolution on to the solid carrier excipient.

In one embodiment of this method the solid carrier is microcrystallinecellulose.

In another embodiment of this method the solvent is 2-pyrrolidone ordimethyl acetamide.

Another aspect of the current invention is a method of controllingparasite infestation in an animal comprising administering to the animala therapeutically effective amount of the composition as describedabove.

Another aspect of the current invention is a solid oral pharmaceuticalcomposition comprising an isoxazoline compound of Formula (I) or a saltor solvate thereof, and 2-pyrrolidone.

In one embodiment the isoxazoline compound is fluralaner.

In one embodiment the isoxazoline compound is4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.

In one embodiment the isoxazoline compound is afoxolaner.

In one embodiment the isoxazoline compound is4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.

In one embodiment the isoxazoline compound is5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.

In one embodiment the solid oral pharmaceutical composition is a softchewable veterinary pharmaceutical composition for oral administration.

Another aspect of the current invention is a method of controllingparasite infestation in an animal comprising administering to the animala therapeutically effective amount of the composition as describedabove.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1—mean plasma concentration of the CPBI compound fluralaneradministered orally to dogs.

FIG. 2—mean plasma concentration of the isoxazoline compounds afoxolanerand-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamideadministered orally to dogs.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the formulation of a solid oral dosageform (sometimes referred to as solid pharmaceutical composition orformulation) containing an isoxazoline compound of Formula (I) (asdescribed below), that provides significantly improved bioavailabilityof such isoxazoline compound after administration to an animal.

Specifically, in this formulation the isoxazoline compound of Formula(I) is dissolved in a solvent. This drug solution is then adsorbed ontoa solid carrier which is incorporated into a traditional solid oraldosage form. Utilizing pre-dissolved isoxazoline compounds of Formula(I) in the formulation significantly improves the bioavailability of theactive drug substance compared to traditional solid oral dosage formscontaining the active drug substance incorporated as a solid.

As indicated in the example the inventors discovered, that withdimethylacetamide (DMAC) as solvent for isoxazoline compounds in a solidoral dosage form similar pharmacokinetic profiles were obtained when itwas s dosed at a lower dose compared to dosage forms with the activeincorporated in higher dosage as a solid.

When 2-pyrrolidone (2-pyrol) was utilized as the solvent in theformulation, significantly higher plasma levels were observed comparedto the control, even with the formulation comprising an isoxazolinecompound dosed at a lower dose.

This formulation approach provides unexpectedly significant improvementin bioavailability, enabling a significantly lower dosage required toachieve similar or superior pharmacokinetic profiles. Hence, similarblood levels can be achieved that lead to similar effectiveness tocontrol parasites but with a reduced dosage of the isoxazoline compound.

The solid oral dosage form according to the invention comprises anisoxazoline compound of the Formula (I)

wherein

R¹=halogen, CF₃, OCF₃, CN,

n=integer from 0 to 3, preferably 1, 2 or 3,

R²=C₁-C₃-haloalkyl, preferably CF₃ or CF₂Cl,

T=5- or 6-membered ring, which is optionally substituted by one or moreradicals Y,

Y=methyl, halomethyl, halogen, CN, NO₂, NH₂—C═S, or two adjacentradicals Y form together a chain CH—CH═CH—CH, N—CH═CH—CH, CH—N═CH—CH,CH—CH═N—CH, or CH—CH═CH—N, HC═HC—CH, CH—CH═CH, CH═CH—N, N—CH═CH;

Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals Z^(A), Z^(B) Z^(D);

X=CH₂, CH(CH₃), CH(CN), CO, CS,

R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

R⁴=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl,haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl,propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl,methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl,ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl; or

R³ and R⁴ together form a substituent selected from the group consistingof:

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃);

or a salt or solvate thereof, a solid carrier and a solvent, wherein thesolvent is selected from 2-pyrrolidone, dimethylacetamide or mixturesthereof.

In one preferred embodiment in Formula (I) T is selected from

wherein in T-1, T-3 and T-4 the radical Y is hydrogen, halogen, methyl,halomethyl, ethyl, haloethyl.

In an preferred embodiment in Formula (I) Q is selected from

Wherein R³, R⁴, X and Z^(A) are as defined above.

Preferred compounds of Formula (I) are:

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, 5Cl CF₃ CH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂CH₂OCH₃ H T-2 —Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-Cl, 5ClCF₃ CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O)3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-73-Cl, 5Cl CF₃ — — T-2 — Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-73-Cl, 5Cl CF₃ — — T-2 — Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CC H T-3 CH₃ Q-1 — C(O) 3-Cl,5Cl CF₃ CH₂C(O)NHCH₂CN H T-3 CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ HT-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O)3-Cl, 4-Cl, CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 4-Cl,CF₃ CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 4-F, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃H T-3 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃CH₂C(O)NHCH₂CF₃ CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 —C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O)3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃CH₂CH₂SCH₃ H T-21 — Q-1 — C(O) 3-Cl, 4-Cl, CF₃ C(O)CH₃ H T-22 F Q-1 —CH₂ 5-Cl 3-Cl, 4-Cl, CF₃ C(O)CH(CH₃)₂ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl,4-Cl, CF₃ C(O)-cyclo-propyl H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-F, 5-Cl CF₃C(O)CH₃ H T-22 F Q-1 — CH₂ 3-Cl, 4-Cl, CF₃ C(O)CH₂CH₃ H T-22 F Q-1 — CH₂5-Cl 3-Cl, 4-F, 5-Cl CF₃ C(O)CH₃ H T-22 Cl Q-1 — CH₂ 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ HT-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (Z) H T-1 CH₃ Q-1 — C(O) 3-Cl,5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

Especially preferred compounds of Formula (I) are

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, 5Cl CF₃ CH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂CH₂OCH₃ H T-2 —Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ HT-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2— Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2— Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl,5Cl CF₃ CH₂C(O)NHCH₂CC H T-3 CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CNH T-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 —C(O) 3-Cl, 4-Cl, CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl,4-F, CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ CH₃T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂CH₂SCH₃ H T-21 —Q-1 — C(O) 3-Cl, 4-Cl, CF₃ C(O)CH₃ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-Cl,CF₃ C(O)CH(CH₃)₂ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-Cl, CF₃C(O)-cyclo-propyl H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-F, CF₃ C(O)CH₃ H T-22F Q-1 — CH₂ 5-Cl 3-Cl, 4-Cl, CF₃ C(O)CH₂CH₃ H T-22 F Q-1 — CH₂ 5-Cl3-Cl, 4-F, CF₃ C(O)CH₃ H T-22 Cl Q-1 — CH₂ 5-Cl 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (Z) H T-1 CH₃Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

A more preferred compound has the Formula (II),

wherein

R^(1a), R^(1b), R^(1c) are independently from each other hydrogen, C₁ orCF₃, preferably R^(1a) and R^(1c) are C₁ or CF₃ and R^(1b) is hydrogen,

T is

wherein Y is methyl, bromine, Cl, F, CN or C(S)NH₂, and

Q is as described above.

In another preferred embodiment in R³ is H and R⁴ is—CH₂—C(O)—NH—CH₂—CF₃, —CH₂—C(O)—NH—CH₂—CH₃, —CH₂—CH₂—CF₃ or —CH₂—CF₃.

In one embodiment the compound of Formula (I) is4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(CAS RN 864731-61-3—USAN fluralaner).

In another embodiment the compound of Formula (I) is(Z)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide(CAS RN 928789-76-8).

In another embodiment the compound of Formula (I) is4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide(CAS RN 1164267-94-0) that was disclosed in WO2009/0080250.

In another embodiment the compound of Formula (I) is4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazoly]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide(CAS RN 1093861-60-9, USAN—afoxolaner) that was disclosed inWO2007/079162-.

In another embodiment the compound of Formula (I) is5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide(CAS RN 1231754-09-8) that was disclosed in WO2010/070068.

An especially preferred compound is

Especially preferred compounds of Formula (II) are:

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2— Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 —Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 —Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-CF₃,5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 4-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃H T-3 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ HT-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O)3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1(Z) H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

Isoxazoline compounds are known in the art and these compounds and theiruse as parasiticide are described, for example, in US patent applicationNo. US 2007/0066617, and International Patent applications WO2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075,WO2009/080250, WO 2010/070068, WO 2010/079077, WO 2011/075591 and WO2011/124998, the disclosures of which, as well as the references citedherein, are incorporated by reference. This class of compounds is knownto possess excellent activity against ectoparasites such as ticks andfleas.

The isoxazoline compounds may exist in various isomeric forms. Areference to an isoxazoline compound always includes all possibleisomeric forms of such compound. Unless otherwise stated, a compoundstructure that does not indicate a particular conformation is intendedto encompass compositions of all the possible conformational isomers ofthe compound, as well as compositions comprising fewer than all thepossible conformational isomers. In some embodiments, the compound is achiral compound. In some embodiments, the compound is a non-chiralcompound.

Isoxazoline compounds of Formula (I) can be prepared according to one orother of the processes described e.g. in Patent Applications US2007/0066617, WO 2007/079162, WO 2009/002809, WO 2009/080250, WO2010/070068, WO 2010/079077, 2011/075591 and WO 2011/124998 or any otherprocess coming within the competence of a person skilled in the art whois an expert in chemical synthesis. For the chemical preparation of theproducts of the invention, a person skilled in the art is regarded ashaving at his disposal, inter alia, the entire contents of “ChemicalAbstracts” and of the documents which are cited therein.

The formulations according to the invention are effective for longdurations of time in the treatment of ectoparasites of mammals and, inparticular, of fleas and ticks in small mammals such as dogs and cats.

The amount of the isoxazoline compound of Formula (I) in the formulationmay be in the range of 1-15% w/w. In an alternative embodiment theamount of such compound may be in the range of 2.0-7.5% w/w. Thepreferred range is 3.0-4.5% w/w.

In one embodiment, the composition comprises a solid carrier, e.g.microcrystalline cellulose, colloidal silicone dioxide, polyvinylpyrrolidone or other solid carrier excipient with appropriatecharacteristic behaviours.

In one embodiment the solid carrier is microcrystalline cellulose(10.0-50.0% w/w, preferred 15.0-25.0% w/w).

In the formulation according to the invention one preferred solvent is apyrrolidone solvent, especially 2-pyrrolidone. Alternatively otherpyrrolidone solvents such as N-methylpyrrolidone can be used.

Another preferred solvent is dimethyl acetamide (DMAC). The preferredrange of dimethyl acetamide (DMAC) is 2.0-35.0% w/w. Alternativesolvents for use in the current invention dimethyl sulfoxide, dimethylformamide, diethylene glycol monoethyl ether, ethyl lactate, ethylenemonomethyl ether, glycofurol, N,N-diethyl-m-toluamide (DEET) or othersolvent with suitable solubility for the compound of Formula (I).Solvent combinations may also be utilized in the formulation accordingto the invention. The preferred range of such other solvents is2.0-35.0% w/w.

The amount of the pyrrolidone solvent, especially 2-pyrrolidone in theformulation may be in the range of 2.5-30.0% w/w. The preferred range is7.0-12.0% w/w. The preferred range of other dimethyl acetamide is2.0-35.0% w/w.

In one embodiment, the solid oral dosage form is a soft chew. In anotherembodiment, the solid oral dosage form is a conventional (hard) tablet.Such tablet can include a coating or can include excipients for extendedrelease that are known in the art. In yet another embodiment, granulesfor oral administration or capsules are employed.

“Soft chew” or “Soft chewable veterinary pharmaceutical product” isintended to mean a product which is solid at room temperature and thatis soft to chew and which is functionally chewy because the product hassome plastic texture during the process of mastication in the mouth.Such soft chews have a softness that is similar to a cooked ground meatpatty.

In soft chew formulations the forming agent is important for the textureof the soft chew and the possibility to form single soft chews from thedough that stay intact and separate. Forming agents are agents providingtexture to the soft chew product, like for example polyethylene glycol(PEG), microcrystalline wax, cetyl alcohol or polyvinylpyrrolidone(PVP). In an embodiment, the forming agent is polyethylene glycol (PEG).Moreover, depending upon the desired consistency of the soft chew,different molecular weight PEG may be utilized. In an embodiment, PEG8000 is utilized. However, the PEG chosen is a matter of choice and themolecular weight may be higher or lower than 8000, but preferably higherthan 600. Alternatively PEG 3500 might be used.

In an embodiment, the forming agent comprises about 3.0% to about 35%w/w of the pharmaceutical composition. In an alternate embodiment, aforming agent comprises about 4.5% to about 30% w/w % of thepharmaceutical composition. In an alternate embodiment, a forming agentcomprises about 10% to about 20% w/w of the pharmaceutical composition.In case the forming agent is polyvinylpyrrolidone e.g. 2, 4, 5, 6 or 9%w/w are present in the soft chew.

A preferred formulation for the solid oral pharmaceutical compositionincludes:

-   -   4.4% w/w compound of Formula (I), especially fluralaner    -   10.5% w/w 2-pyrrolidone    -   25.0% w/w microcrystalline cellulose    -   5.1% w/w sodium starch glycolate    -   15.0% w/w flavour    -   2.0% w/w sodium lauryl sulphate    -   2.5% w/w sodium pamoate    -   0.5% w/w aspartame    -   0.5% w/w magnesium stearate    -   1.5% w/w glycerol    -   17.25% w/w soybean oil    -   15.75% w/w PEG8000

The amount of glycerol in the formulation may range from 0-12.0% withthe preferred range of 0.5-10.0%. Soybean oil amounts may range from5.0-25.0% with the preferred range of 10.0-22.0%. Desired ranges of theother excipients include sodium starch glycolate (2.0-15.0%), flavor(5-25%), sodium lauryl sulfate (0.05-5.0%), sodium pamoate (0.01-5.0%),aspartame (0.01-2.0%), and magnesium stearate (0.01-2.0%).

The formulation according to the current invention conventionallyfurther comprise physiologically acceptable formulation excipients knownin the art e.g. as described in “Gennaro, Remington: The Science andPractice of Pharmacy” (20th Edition, 2000) incorporated by referenceherein. All such ingredients, carriers and excipients must besubstantially pharmaceutically or veterinary pure and non-toxic in theamounts employed and must be compatible with the pharmaceutically activeingredients.

Additional excipients that can be present in the formulation are e.g.one or more fillers, one or more flavours, or sugar components,surfactants, stabilizers, flow agents, disintegration agents,preservatives and/or lubricating agents.

This invention is also directed to formulations as described above withcombinations comprising more than one pharmaceutically activeingredient, e.g. in addition to the compound of Formula (I) anothercompound of Formula (I) or a pharmaceutically active ingredient with adifferent structure.

Preferred combinations comprising active ingredients selected from thegroup consisting of isoxazoline compounds of Formula (I) or (II) andavermectins and milbemycins. In one embodiment the formulation,especially soft chew comprises a combination of an isoxazoline compoundof Formula (I), especially fluralaner or afoxolaner, with ivermectin. Inanother embodiment the soft chew comprises a combination of anisoxazoline compound of Formula (I), especially fluralaner porafoxolaner, with milbemycin or with moxidectin.

Other combinations of the present invention can include insect or acaridrrowth regulators (AGRs or IGRs) such as e.g. fenoxycarb, lufenuron,diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine,methoprene, pyriproxyfen etc., thereby providing both initial andsustained control of parasites (at all stages of insect development,including eggs) on the animal subject, as well as within the environmentof the animal subject.

The inventors discovered that oral solid dosage forms of isoxazolinecompounds of Formula (I) as described above, especially of fluralaner,afoxoloaner can be produced that result in a higher bioavailability ofthe isoxazoline compound after administration to animals. In suchmethods the isoxazoline compound of Formula (I) is first dissolved in asuitable solvent (e.g. 2-pyrol or DMAC) and then adhered to a solidcarrier (e.g. microcrystalline cellulose). Such process can be used ingeneral for various solid oral dosage forms such as hard tablets,granules, capsules or soft chews (soft chewable tablets).

A general method for preparing a solid oral dosage form, such as a softchewable tablet formulation comprises the steps of:

-   -   1. Dissolve the isoxazoline compound (e.g. fluralaner or        afoxolaner) in the solvent (e.g. 2-pyrrolidone) to form a        solution.    -   2. Add the isoxazoline solution to the solid carrier (e.g.        microcrystalline cellulose) and mix to form a first dry mixture.    -   3. Add all other dry excipients to the first dry mixture and mix        to form a second dry mixture.    -   4. Add liquid ingredients, glycerol and soybean oil, to the        second dry mixture. Mix to form wet mass.    -   5. Melt a wax (e.g. polyethylene glycol 8000) and add to the wet        mass. Mix well to form the final bulk mass.    -   6. Form appropriately sized chewable tablets

In an embodiment the tablets may be formed from the final bulk massutilizing a forming machine. Alternatively, the tablets may be formed byother means known in the art. For example, the tablets may be formed byhand.

Methods of Using the Solid Oral Pharmaceutical Compositions

In one embodiment the product of the invention is intended for use forcontrolling a parasitic insect-, acarid and/or helminth, especiallyparasitic insect and/or acarid infestation. The term “controlling aparasitic insect- and/or acarid infestation” refers to preventing,reducing or eliminating an infestation by such parasites on animalspreferably by killing the insects and/or acarids or nematode parasiteswithin hours or days.

The term “parasitic insect- and acarid” refers to ectoparasites e.g.insect and acarine pests that commonly infest or infect animals.Examples of such ectoparasites include the egg, larval, pupal, nymphaland adult stages of lice, fleas, mosquitoes, mites, ticks, and biting ornuisance fly species. Especially important are fleas and ticks,especially their adult stages.

Examples of invertebrate parasitic pests controlled by administering thesolid oral formulation of this invention to an animal to be protectedinclude ectoparasites (arthropods, acarines, etc) and endoparasites(helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans,etc.).

In particular, the formulations of this invention are effective againstectoparasites including: flies such as Haematobia (Lyperosia) irritans(horn fly), Stomoxys calcitrans (stable fly), Simulium spp. (blackfly),Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Muscaautumnalis (face fly), Musca domestica (house fly), Morellia simplex(sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypodermalineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphoraspp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly),Culicoides spp. (midges), Hippobosca equine, Gastrophilus instestinalis,Gastrophilus haemorrhoidalis and Gastrophilus naslis; lice such asBovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicolasubrostratus, Heterodoxus spiniger, Lignonathus setosus and Trichodectescanis; keds such as Melophagus ovinus; mites such as Psoroptes spp.,Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp.,Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites);ticks such as Ixodes spp., Boophilus spp., Rhipicephalus spp., Amblyommaspp., Dermacentor spp., Hyalomma spp. and Haemaphysalis spp.; and fleassuch as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dogflea).

In general, the formulations according to the invention will contain aneffective amount of the isoxazoline compounds of Formula (I) as definedabove, meaning a non-toxic but sufficient amount to provide the desiredcontrol effect. A person skilled in the art using routineexperimentation may determine an appropriate “effective” amount in anyindividual case. Such an amount will depend on the age, condition,weight and type of the target animal.

The solid oral dosage forms may be formulated to contain an amount ofthe isoxazoline compound of Formula (I) that is adjusted to animals in aspecific weight range. The animals may receive a dosage of the solidoral formulation according to the invention every 2, 3, 4, 5 or 6 monthsor receives a monthly, weekly or daily dosage. The treatment can, forexample, be continuing or seasonal. The time period between treatmentsdepends upon factors such as the parasite(s) being treated, the degreeof infestation, the type of mammal or bird and the environment where itresides. It is well within the skill level of the practitioner todetermine a specific administration period for a particular situation.

The solid oral formulations of the present invention are especiallysuitable for combating parasites that infest mammals (including humans).Mammalian subjects include primates (e.g., monkeys), bovine (e.g.,cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goatsor sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g.,house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, androdents (e.g., guinea pigs, squirrels, rats, mice, gerbils, andhamsters). Of particular note is the embodiment wherein the animals tobe protected are domesticated dogs (i.e. Canis lupus familiaris) anddomestic house cats (i.e. Felis catus).

In some embodiments of this invention, the solid oral formulation of anisoxazoline of Formula (I) is administered to treat parasitoses of ananimal (or make a medicament to treat parasitoses of an animal). Theterm “parasitoses” includes pathologic conditions and diseasesassociated with or caused by one or more ectoparasites directly, suchas, for example, anemia and flea allergy dermatitis. It also includespathologic conditions or diseases associated with caused by one or morevector-transmitted pathogens, such as, for example, Lyme disease,Ehrlichiosis (particularly Canine Ehrlichiosis), and Rocky Mountainspotted fever from vector ticks.

This invention also relates to treatment methods wherein at least anancillary goal of controlling ectoparasites in and/or on an animal is tocontrol an ectoparasitic infestation in an environment that is occupied(periodically or continuously) by the animal. In some such embodiments,for example, the animal is a companion animal (e.g., a cat or dog). Theenvironment may be, for example, a house or other shelter; a room; apen, a stall, or other confinement means; bedding; etc.

This invention also is directed to kits that are, for example, suitablefor use in performing the treatment methods described above. In general,such a kit will comprise an oral solid formulation according to theinvention comprising a therapeutically effective amount of a isoxazolineof Formula (I), and an additional component(s). The additionalcomponent(s) may be, for example, one or more of the following: adiagnostic tool, instructions for administering the composition, anapparatus for administering the composition, a container comprising anexcipient or other active ingredient to be mixed or administered incombination with the composition, or a memory aid (e.g., a stamp toadhere to a calendar to remind an animal owner of a time to administer asubsequent dose of the composition).

As used herein, the term “w/w” designates weight/weight, the term “w/v”designates weight/volume, and the term “mg/kg” designates milligrams perkilogram of body weight. As used herein, % w/w represents the percentageby weight of an ingredient in the recipe of the product.

The invention having been fully described, its practice is illustratedby the examples provided below. The examples do not limit the scope ofthe invention, which is defined entirely by the appended claims.

EXAMPLES Example 1

An embodiment for a direct compression tablet containing two activeingredients includes:

0.015% w/w ivermectin

2.5% w/w fluralaner

0.1% w/w citric acid

0.5% w/w Cremaphor RH40

4.5% w/w 2-pyrrolidone

50.0% w/w microcrystalline cellulose

33.735% w/w corn starch

8.0% w/w flavor

0.5% magnesium stearate

0.1% w/w aspartame

0.05% w/w red iron oxide

Example 2

An embodiment for soft chewable tablets containing two activeingredients includes:

0.42% w/w moxidectin

1.67% w/w fluralaner

0.2% w/w citric acid

4.0% w/w 2-pyrol

10.0% w/w microcrystalline cellulose

3.0% w/w flavor

0.2% w/w aspartame

4.0% w/w Klucel

30.51% w/w soy grits

4.0% w/w propylene glycol

4.0% w/w Miglyol 812

8.0% w/w cetyl alcohol

10.0% w/w Cremaphor RH40

20.0% w/w sodium starch glycolate

Example 3

Additional embodiments for the soft chewable tablets include:

5.333% w/w fluralaner

9.0% w/w 2-pyrrolidone

11.0% w/w microcrystalline cellulose

5.0% w/w Pluronic 127

5.0% w/w sodium lauryl sulfate

10.0% w/w flavor

5.0% w/w sodium starch glycolate

16.667% soy grits

2.0% w/w Labrasol

13.0% w/w Labrafac PG

18.0% w/w PEG3350

Example 4

7.25% w/w fluralaner

10.5% w/w 2-pyrrolidone

22.75% microcrystalline cellulose

2.0% colloidal silicone dioxide

3.5% w/w Lutrol Micro 127

3.5% w/w sodium lauryl sulfate

15.0% w/w flavor

0.5% w/w aspartame

0.5% w/w magnesium stearate

2.0% w/w Labrasol

14.75% w/w soybean oil

15.25% w/w PEG8000

Example 5

7.5% w/w fluralaner

7.0% w/w dimethyl acetamide

23.5% microcrystalline cellulose

15.0% w/w flavor

7.5% w/w sodium starch glycolate

3.5% w/w sodium lauryl sulfate

2.0% w/w sodium pamoate

0.5% w/w magnesium stearate

0.5% w/w aspartame

7.0% w/w glycerol

10.0% w/w soybean oil

16.0% w/w PEG8000

Example 6

4.4% w/w fluralaner

10.5% w/w 2-pyrrolidone

25.0% microcrystalline cellulose

15.0% w/w flavor

5.1% w/w sodium starch glycolate

3.5% w/w sodium lauryl sulfate

2.5% w/w sodium pamoate

0.5% w/w magnesium stearate

0.5% w/w aspartame

3.0% w/w glycerol

14.25% w/w soybean oil

15.75% w/w PEG8000

Example 7

Multiple formulations were evaluated for their impact on bioavailabilityof Fluralaner when formulated in a soft chewable tablet.

The descriptions of selected formulations are listed below.

TABLE 1 Control 2-Pyrol DMAC Excipient Formulation FormulationFormulation fluralaner 13.64%  4.4% 7.5% 2-pyrrollidone 10.5% dimethylacetamide 7.0% Avicel PH102 25.0%  23.5%  flavor 20.0%  15.0% 15.0%  corn starch 16.06%  sodium starch glycolate 5.1% 7.5% sucrose7.0% sodium lauryl sulfate 2.0% 3.5% 3.5% sodium pamoate 2.0% 2.5% 2.0%magnesium stearate 0.75%  0.5% 0.5% aspartame 0.25%  0.5% 0.5% glycerol7.5% 3.0% 7.0% soybean oil 12.3%  14.25%  10.0%  Polyethylene Glycol3350 18.5%  Polyethylene Glycol 8000 15.75%  16.0% 

Dimethylacetamide (DMAC) is a good solvent for the active (A-1443) witha solubility of 791.5 mg/mL. However, when utilized in this type offormulation approach, similar pharmacokinetic profiles were obtainedcompared to chewable tablets with the active incorporated as a solid(control). Given that the DMAC formulation was dosed at a lower dose (15mg/kg compared to 25 mg/kg for the control), these results areimprovements in dose adjusted pharmacokinetic measurements (Cmax andAUC) over the control (see Table 2 and FIG. 1).

When 2-pyrrolidone (2-pyrol) was utilized as the solvent in theformulation (solubility 775.41 mg/mL), significantly higher plasmalevels were observed compared to the control, even with the formulationdosed at a lower dose (15 mg/kg compared to 25 mg/kg for the control).Dose normalized pharmacokinetic measurements (Cmax and AUC) for the2-pyrol formulation are more than double that of the DMAC formulationand more than triple that of the control (see Table 2 and FIG. 1). Theseresults were unexpected.

This formulation approach provides significant improvement inbioavailability, enabling a significantly lower dosage required toachieve similar to superior pharmacokinetic profiles.

TABLE 2 Control 2-Pyrol DMAC Pharmacokinetic Parameter FormulationFormulation Formulation T_(1/2) 20.3 21.6 21.3 (days) Tmax 40.8 55.248.8 (hours) Cmax 2832 5973 2511 (ng/mL) Dose 25 15 15 (mg/kg) Cmax/Dose113 398 167 (kg * ng/mL/mg) AUC_(0-inf) 1501420 3562496 1531455 (h *ng/mL) AUC_(0-inf)/Dose 60057 237500 102097 (h * kg * ng/mL/mg)Bioavailability 27.8% 109.8% 47.2%

Example 8 Pharmacokinetic Profile Following Oral Administration ofChewable Formulations of Isoxazoline Compounds

The objective of this study is to compare the blood plasmapharmacokinetic profile of three different isoxazoline compounds in twodifferent chewable formulations after a single oral (PO) administrationof in dogs.

Test Formulations:

The following compounds were formulated according to the invention.Specifically, the isoxazoline compound was first dissolved in a solvent,i.e. 2-pyrrolidone. This drug solution was then adsorbed onto the solidcarrier, i.e. microcrystalline cellulose, which was incorporated into asolid oral dosage form as described in the specification with excipientsas described in Table 3. Comparative example formulation ID No. 13-009,13-011 and 13-013 contain the active drug substance incorporated as asolid that was manufactured as described in general in the specificationwithout prior pre-dissolving the active ingredient and adsorption to thesolid carrier.

TABLE 3 Test formulations Excipient 13-009 13-010 13-011 13-012 13-01313-014 Compound A 13.64%  4.27% Compound B 13.64%  4.27% Compound C13.64%  4.27% 2-pyrrolidone 10.19% 10.19% 10.19% microcrystalline 24.27%24.27% 24.27% cellulose sodium starch  4.95%  4.95%  4.95% glycolate  flavor  20.0% 14.56%  20.0% 14.56%  20.0% 14.56% sucrose   7.0%  7.0% 7.0% corn starch 16.06% 16.06% 16.06% sodium lauryl  2.0%  3.4%  2.0% 3.4%  2.0%  3.4% sulfate       sodium  2.0%  2.43%  2.0%  2.43%  2.0% 2.43% pamoate       magnesium  0.75%  0.49%  0.75%  0.49%  0.75%  0.49%stearate             aspartame  0.25%  0.49%  0.25%  0.49%  0.25%  0.49%glycerin  7.5%  2.91%  7.5%  2.91%  7.5%  2.91% soybean oil  12.3%16.75%  12.3% 16.75%  12.3% 16.75% PEG 3350  18.5%  18.5%  18.5% PEG8000 15.29% 15.29% 15.29%

Study Design

The test compounds were administered orally to four beagle dogs per dosegroup for a total of twenty-four dogs.

Experimental Design: Randomized Complete Block Design

TABLE 4 Study Design Treatment No. of Formulation Compoud DoseFormulation ID dogs ID ID (mg/kg) Type^(2,3) 1 4 13-009 A 25 ControlChew 2 4 13-010 A 10 Alternate Chew 3 4 13-011 B 25 Control Chew 4 413-012 B 10 Alternate Chew 5 4 13-013 C 25 Control Chew 6 4 13-014 C 10Alternate Chew ²Control Chew-compound is not dissolved when formulatedinto chew (comparative example). ³Alternate Chew-compound is dissolvedwhen formulated into chew

Each animal was administered the tablet or chew by placing it in theback of the oral cavity over the tongue to initiate swallowing.

Plasma was obtained from the collected blood samples and analyzed forconcentrations of the test compounds. Individual blood samples(approximately 4.5 mL per sample) were taken via jugular venipunctureinto sodium-citrate tubes from all dogs for drug analysis. Blood sampleswere collected at the following time points: pretreatment (within 2 hprior to dosing) and approximately 1, 2, 4, 6, 8, 24, 48, 72 hours afterdosing (±15 min). A final blood sample was taken from each dog on Day 7(±2 h after the time of dosing on Day 0).

Results:

When 2-pyrrolidone (2-pyrol) was utilized as the solvent in theformulation (alternate chew), similar or even higher plasma levels wereobserved compared to the control chew, even with the formulation dosedat a lower dose (10 mg/kg compared to 25 mg/kg for the control)—see FIG.2.

Pharmacokinetic analysis was performed on the plasma concentration datawith the computer program Pharsight WinNonlin Enterprise, Version 4.0.1,or more recent update (Model 200: plasma data, extravascular input).

Dose normalized pharmacokinetic measurements (Cmax and AUC) for the2-pyrol formulation (alternate chew) are much higher, in some cases morethan double to five times that of the control formulation (see Table 5).

This formulation approach provides significant improvement in thebioavailability relative to the control formulation, enabling asignificantly lower dosage required to achieve similar to superiorpharmacokinetic profiles. These results were unexpected.

TABLE 5 Pharmacokinetic Control Dissolved Control Dissolved ControlDissolved Parameter Compound A Compound B Compound C Dose 25 10 25 10 2510 (mg/kg) Tmax 5.0 15.5 27.5 15.5 (h) Cmax 19.2 17.1 4340 3213 15892538 (ng/mL) Cmax/Dose 0.768 1.71 174 321 63.5 254 (kg*ng/mL/mg)AUC_((0-168h)) ND ND 416522 334163 164332 326601 (h*ng/mL)AUC_((0-168h))/Dose ND ND 16661 33416 6573 32660 (h*kg*ng/mL/mg)

Example 9 Efficacy Against Brown Dog Ticks (R. sanguineus) on Dogs

A solid pharmaceutical composition according to the invention with thefollowing excipients was prepared.

Excipient Composition (% w/w) Fluralaner 4.27% 2-pyrrolidone 10.19%microcrystalline cellulose 24.27% sodium starch glycolate 4.95% flavor14.56% sodium lauryl sulfate 3.40% sodium pamoate 2.43% aspartame 0.49%magnesium stearate 0.49% glycerol 2.91% soybean oil 16.75% PolyethyleneGlycol 8000 15.29%

Dogs were randomly assigned to 4 treatment groups of 8 animals each, andone untreated control group of 8 animals. The dogs in the treatmentgroups were treated with the composition as described above on Day Zeroas shown in Table 6:

TABLE 6 Treatment Groups Group Treatment A Untreated control B 4.27%fluralaner chewable tablet  8 mg/kg bw C 4.27% fluralaner chewabletablet 10 mg/kg bw D 4.27% fluralaner chewable tablet 12 mg/kg bw E4.27% fluralaner chewable tablet 20 mg/kg bw

The dogs were infested on Day −2 with approximately 50 adult unfed ticks(R. sanguineus) and on Day 28 and 56. Ticks were counted approximately48 h post infestation and on Days 30 and 58 (approximately 48 hour aftereach post-treatment re-infestation) to evaluate the acaricidal activityin the treated groups.

Table 7 Shows the Observed Tick Counts:

TABLE 7 Brown Dog Ticks (R. sanguineus) on dogs- Tick counts - Group Day2 Day 30 Day 58 A 21.25 23 25.9 B 0 0 0 C 0.125 0 0 D 0 0 1.13 E 0 0 0

What is claimed is:
 1. A soft chewable veterinary pharmaceutical composition for oral administration comprising an isoxazoline compound of Formula (I)

wherein R¹=halogen, CF₃, OCF₃, CN, n=integer from 0 to 3, preferably 1, 2 or 3, R²=C₁-C₃-haloalkyl, preferably CF₃ or CF₂Cl, T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y, Y=methyl, halomethyl, halogen, CN, NO₂, NH₂—C═S, or two adjacent radicals Y form together a chain, especially a three or four membered chain; Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals; X=CH₂, CH(CH₃), CH(CN), CO, CS, R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl,

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃); R⁴=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; Or R³ and R⁴ together form a substituent selected from the group consisting of:

or a salt or solvate thereof, a solid carrier and a solvent wherein the solvent is selected from 2-pyrrolidone, dimethyl acetamide or mixtures thereof.
 2. (canceled)
 3. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the solid carrier is microcrystalline cellulose.
 4. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the solvent is 2-pyrrolidone.
 5. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the solvent is dimethyl acetamide.
 6. (canceled)
 7. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the isoxazoline compound is fluralaner.
 8. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.
 9. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the isoxazoline compound is afoxolaner.
 10. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the isoxazoline compound is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.
 11. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.
 12. The soft chewable veterinary pharmaceutical composition of claim 1 wherein the composition comprises an additional pharmaceutically active compound.
 13. The soft chewable veterinary pharmaceutical composition of claim 8 comprising an additional pharmaceutically active compound wherein the additional pharmaceutically active compound is a macrocyclic lactone selected from the group of ivermectin, milbemycin, and moxidectin.
 14. A soft chewable veterinary pharmaceutical composition according to claim 1, wherein the composition comprises an isoxazoline compound of Formula (I) or a salt or solvate thereof, 2-pyrrolidone, Microcrystalline cellulose, Sodium starch glycolate, Sodium lauryl sulfate, Sodium Pamoate, Magnesium Stearate, Aspartame, Glycerol, Soybean Oil, and Polyethylene Glycol.
 15. A soft chewable veterinary pharmaceutical composition according to claim 1 wherein the composition comprises an isoxazoline compound of Formula (I) or a salt or solvate thereof, dimethyl acetamide, Microcrystalline cellulose, Sodium starch glycolate, Sodium lauryl sulfate, Sodium Pamoate, Magnesium Stearate, Aspartame, Glycerol, Soybean Oil, and Polyethylene Glycol.
 16. A method of preparing the composition of claim 1 comprising dissolving the isoxazoline compound in the solvent and then adsorbing the resulting solution on to the solid carrier excipient.
 17. The method of claim 12, where the solid carrier excipient is microcrystalline cellulose. 18-20. (canceled)
 21. A method of controlling parasite infestation in an animal comprising administering to the animal a therapeutically effective amount of the composition of claim
 1. 22. (canceled)
 23. The method of claim 21 wherein the isoxazoline compound is fluralaner. 24-29. (canceled)
 30. The method of claim 16, where the solvent is 2-pyrrolidone.
 31. The method of claim 16, where the solvent is dimethyl acetamide.
 32. The method of claim 12 wherein the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.
 33. The method of claim 12 wherein the isoxazoline compound is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.
 34. The method of claim 12 wherein the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.
 35. The method of claim 12 wherein the isoxazoline compound is fluralaner.
 36. The method of claim 12 wherein the isoxazoline compound is afoxolaner. 